BIOCHEMICAL AND PHARMACOLOGICAL CHARACTERIZATION OF SR141716A, THE FIRST POTENT AND SELECTIVE BRAIN CANNABINOID RECEPTOR ANTAGONIST

SR141716A is a selective, potent and orally active antagonist of the b rain cannabinoid receptor with a long duration of action. This compoun d shows high affinity for the central cannabinoid receptor (K-i=2 nM), displays low affinity for the peripheral cannabinoid receptor (K-i>10 00 nM). In vitro, SR141716A antagonizes the inhibitory effects of cann abinoid receptor agonists on both mouse vas deferens contractions and dopamine-stimulated adenylyl cyclase activities in rat brain membranes . After oral administration SR141716A totally inhibited the ex vivo [H -3]-CP55,940 binding to cerebral membranes with a ED(50) value of 3.5 mg/kg. Furthermore SR141716A antagonizes the classical pharmacological responses elicited by cannabinoid receptor agonists. In addition, SR1 41716A reverses the inhibitory effect of WIN55212-2 on isoniazid-induc ed elevation of cGMP in rat cerebellum. This compound will provide a p owerful tool for studying the in vivo functions of the anandamide/cann abinoid system.